ABSTRACT Ovarian cancer continues to represent an unmet clinical need: 2/3 of the diagnosed patients eventually die of the disease and new therapeutics has made almost no incremental contributions over the past decade. The presence of MUC16 (which encodes the CA125 antigen) is a hallmark of High Grade Serous Cancer of the Ovary with its own adverse outcome effect and undiscovered biology. This project exploits the relatively selective nature of MUC16 to unravel complex biology and expose fundamental cancer weaknesses for therapeutic intervention. While the circulating CA125 has been targeted by therapeutic antibody and anti-idiotype strategies, these prior interventions did not focus on the most proximal portions of MUC16 nor its novel pathogenic effects. The project has four specific aims: Specific Aim 1: To interrogate the glycosylation dependent mechanism(s) of MUC16 transformation in 3T3 cells and the enhanced virulence of MUC16 + human ovarian cancer cells. Specific Aim 2: To utilize MUC16 antibodies and single chain Fcv constructs targeting the retained ?ectodomain? to develop radiotracers and radiotherapies for ovarian cancer. Specific Aim 3: To explore and validate the impact of anti-glycosylated MUC16 antibodies through a) in vitro studies, b) in tumor bearing animals, and c) initiate the development of human anti- MUC16 ab with Eureka, leading to d) a phase O study of a human anti-glycosylated MUC16 antibody. Specific Aim 4: Interactions with other projects including: assistance in MUC16 vaccine development (Pr2), Second generation ab development for CAR T cells (Pr3): and sharing of best ab with and Fc mechanisms between Pr 1 and Pr 4.